The significance of pathology
Pathology is a basic medical course that studies the causes, mechanisms and development of human diseases, as well as the morphological structure, functional and metabolic changes of the body and disease regression during the disease process. Because of this, pathology has been regarded as a “bridge subject” between basic medicine and clinical medicine, which fully demonstrates its irreplaceable and important role in medicine, which is determined by the nature and tasks of pathology.
Pathology is not only a basic medical discipline, but also a very practical and clinical discipline, called diagnostic pathology or surgical pathology. The main task is to study and elucidate: (1) etiology, i.e., the causes of diseases including internal and external causes and their interrelationship; (2) pathogenesis, i.e., the specific links, mechanisms and processes leading to the occurrence and development of diseases under the action of etiology; (3) pathological changes or lesions, i.e., the functional metabolism of the body during the development of diseases. (3) pathological changes or lesions, i.e., the functional metabolic and morphological structural changes in the body and the relationship between these changes and clinical manifestations (symptoms and signs) during the development of the disease – the clinicopathological linkage; (4) disease regression and outcome, etc.
Pathology of prostate cancer
Most prostate cancers are follicular adenocarcinomas. Uncommon histologic variants or types of prostate cancer account for approximately 5% to 10% of cancers that occur in the prostate.
Ductal adenocarcinoma
The ductal adenocarcinoma subtype is composed of larger glands lined with tall, pseudostratified columnar cells. This category was originally applied to describe endometrial carcinoma because of its morphologic similarity to the endometrium. Ductal adenocarcinoma alone accounts for 0.2% to 0.8% of prostate cancers. It commonly coexists with a glandular follicular component. Many studies have demonstrated the aggressive nature of ductal adenocarcinoma. Some studies have reported that metastases are present at diagnosis in 25% to 40% of cases, with five-year survival rates ranging from 15% to 43%. Even limited ductal adenocarcinoma on biopsy should be treated with definitive treatment options. Although this tumor does not respond as well to endocrine therapy as follicular adenocarcinoma, anti-androgen therapy may help to alleviate the disease to some extent.
Although the diagnostic term ductal adenocarcinoma is retained to denote the unique clinical and pathologic features of this type of prostate cancer, ductal adenocarcinoma should be graded as Gleason 4+4=8. In some cases, acne-like necrosis is seen, which may be equated to Gleason grade 5 prostate cancer. Ductal adenocarcinoma often presents with a mixture of structural types, including papillary, sieve, single glandular, and solid types.
Immunohistochemically, ductal adenocarcinoma is strongly positive for PSA and PAP. Basal cell-specific high molecular weight cytokeratin (detected by 34βE12) is negative, however, residual ducts are positive for 34βE12. Ductal adenocarcinoma often spreads along the urethra or invades the prostatic ducts with or without interstitial infiltration. Other invasive patterns are similar to those of follicular adenocarcinoma of the prostate, which may infiltrate the periprostatic tissue and metastasize to the pelvic lymph nodes and distant organs. Ductal adenocarcinoma is more likely to metastasize to the lungs and penis.
Atrophic adenocarcinoma
Most prostate cancer cells have abundant cytoplasm. A rare variant of prostate cancer is atrophic adenocarcinoma, which behaves like benign atrophy due to the lack of cytoplasm. Atrophic prostate cancer is usually not associated with treatment, although normal prostate cancer can develop cytoplasmic atrophy after treatment (see Morphology of Prostate Cancer After Treatment).
Pseudoproliferative adenocarcinoma
Pseudohyperplastic prostate cancer resembles BPH because the tumorigenic glands are larger and have branching and papillary infoldings. Identification of this type of cancer is based on the structural features of many glands densely arranged together and the typical malignant nuclei characteristic of the cells. Some pseudoproliferative adenocarcinomas consist of a large number of large glands that are almost dorsal to each other, with straight and flat luminal surfaces and abundant cytoplasm. Benign glands of similar size may have papillary infoldings or atrophy. Some glands in this type of prostate cancer have atypical cells, according to which they can be further differentiated from benign glands. Confirmation of basal cell deficiency by immunohistochemistry is helpful in confirming the diagnosis of pseudohyperplastic adenocarcinoma.
Although pseudohyperplastic adenocarcinoma resembles benign glands, it can coexist with intermediate grade typical prostate cancer and can grow aggressively (e.g., extraprostatic infiltration).
Adenocarcinoma with glomeruloid features
Adenocarcinoma of the prostate with glomeruloid features is characterized by globular clusters of cancer cells in the lumen of the gland, resembling a glomerular structure. The glomerular-like structure of prostate cancer represents a rare, but distinct cancer-specific growth pattern. Glomeruloid features can be a useful clue in the diagnosis of cancer, and this feature is particularly important in some challenging puncture biopsy specimens. This growth pattern is usually seen in high-grade adenocarcinomas, often with extraprostatic infiltration. Glomeruloid features have not been seen in any benign or precancerous lesions (including hyperplasia and intraepithelial neoplasia).
Foamy adenoid adenocarcinoma
Foamy glandular adenocarcinoma is a variant of follicular adenocarcinoma of the prostate, characterized by cancer cells with abundant foamy cytoplasm and a small nuclear-to-plasmic ratio. Although its cell pulp morphology resembles that of a yellow tumor, it does not contain lipids, but vacuoles. This type of prostate adenocarcinoma does not have some of the more typical cytologic features of prostate adenocarcinoma such as enlarged nuclei and obvious nucleoli, therefore, it is often difficult to diagnose as cancer, especially in biopsy specimens. Foamy gland type adenocarcinoma typically presents with small, dark, densely stained nuclei. The nuclei are usually rounded, even more round than those of benign prostate secretory epithelial cells. The histologic features of this type of prostate cancer include densely clustered glands and/or infiltrative glands with dense, powder-stained anaplastic secretions often seen in the lumen. Although foamy glandular adenocarcinoma presents with benign cytologic features, however, in almost all cases it often coexists with the high-grade component of the common type of prostate adenocarcinoma and, therefore, foamy glandular adenocarcinoma is best classified as an intermediate grade carcinoma.
Eosinophilic type adenocarcinoma
Eosinophilic prostate adenocarcinoma consists of large cells containing eosinophilic granular cytoplasm. The tumor cells have round or ovoid nuclei, increased chromatin, and strongly positive PSA staining. A large number of mitochondria are seen in ultrastructural examination. This subtype of carcinoma has been reported to have high Gleason grade, elevated PSA serum, and metastatic foci that resemble the morphology of the primary site.
Lymphoepithelioma-like carcinoma
Lymphoepithelioma-like carcinoma is an undifferentiated carcinoma characterized by a syncytial pattern of malignant tumor cells with a large lymphocytic infiltrate. Malignant mucinous cells stain positively for PSA. It may be accompanied by adenoid adenocarcinoma of the alveolar type. In situ hybridization shows negative for EBV. The clinical significance of this type of carcinoma remains unclear.
Colloid and indolent cell adenocarcinoma
Mucinous adenocarcinoma of the prostate is diagnosed when at least 25% of the resected tumor has an extracellular mucinous lake. Mucinous adenocarcinoma (colloid carcinoma) is one of the least common morphologic types of prostate cancer. In contrast to adenocarcinoma of the bladder, mucinous adenocarcinoma of the prostate rarely contains mucin-positive blastocytes. The biological behavior of mucinous adenocarcinoma of the prostate is aggressive. In the largest number of reported cases, 7 of 12 patients died from the tumor (mean 5 years) and 5 patients survived with the tumor (mean 3 years). Although these tumors are less sensitive to hormones than non-mucinous adenocarcinomas, certain tumors remain effective with anti-androgen therapy. Mucinous adenocarcinoma of the prostate is prone to bone metastases, and serum PSA levels are elevated in patients with advanced disease. There is no consensus on how to score mucinous adenocarcinoma of the prostate. Some scholars suggest a Gleason 8 score, while others suggest ignoring the mucinous component and grading the tumor according to its structural features.
Squamous cell carcinoma
Squamous cell carcinoma can originate in the periurethral glands or prostatic alveoli, the latter of which may arise from differentiation of basal cells in different directions. Approximately 50% of adenosquamous carcinomas occur in patients with prostate cancer after endocrine therapy or radiation therapy. The incidence of squamous cell carcinoma of the prostate is less than 0.6% of all prostate cancers. Adenosquamous carcinoma of the prostate is even less common. Squamous cell carcinoma and adenosquamous carcinoma tend to metastasize early, especially to bone.
Histologically, squamous cell carcinoma must be distinguished from squamous metastasis of the prostate, which can occur after infarction or hormonal therapy. Adenosquamous carcinoma is defined by the coexistence of adenocarcinoma (alveolar type) and squamous cell carcinoma. The adenocarcinoma component usually expresses PSA and PAP, whereas the squamous cell carcinoma component expresses high molecular weight cytokeratin.
Migratory cell carcinoma (uroepithelial carcinoma)
The incidence of primary uroepithelial carcinoma of the prostate is less than 1% of adult prostate tumors. Up to 45% of patients with invasive bladder cancer show tumor involvement of the prostate. Primary uroepithelial carcinoma of the prostate is usually located in the ducts of the proximal prostatic ducts. In many cases, local infiltration is present at the time of diagnosis and replaces the prostate gland. In patients with primary or secondary uroepithelial carcinoma of the prostate, one of the most important prognostic parameters is the presence of interstitial infiltration of the prostate. Such cancers with interstitial infiltration or extraprostatic infiltration have a poor prognosis.
Small cell carcinoma
Small cell carcinoma of the prostate has the same histologic features as small cell carcinoma of the lung. About 50% of cases are a mixture of small cell carcinoma and follicular adenocarcinoma. Neurosecretory granules are seen in individual small cell carcinomas of the prostate. Using immunohistochemical staining techniques, the small cell carcinoma component showed negative PSA and PAP. It is controversial whether thyroid transcription factor-1 (TTF-1) is positive in small cell carcinoma of the prostate.
The average survival of patients with small cell carcinoma of the prostate is less than one year. There is no significant difference in the prognosis of patients with pure small cell carcinoma and small cell carcinoma mixed with adenocarcinoma. The presence of a small cell carcinoma component during the progression of adenocarcinoma of the prostate indicates progression to the end stage of the disease.
Sarcomatoid carcinoma (carcinosarcoma)
There is considerable controversy in the literature regarding the nomenclature and histologic origin of this type of tumor. Some literature considers carcinosarcoma and sarcomatoid carcinoma to be two separate diseases, based primarily on the presence of a specific mesenchymal component in the former. However, because of the similar clinicopathologic features and the poor prognosis of both, they should ideally be considered as one disease. Sarcomatoid carcinoma of the prostate is a rare tumor composed of malignant epithelial and malignant spindle cells and/or mesenchymal components. Sarcomatoid carcinoma may be detected in the pathology specimen initially sent for examination (synchronous presentation) or the patient may have a history of adenocarcinoma of the prostate treated with radiotherapy and/or hormonal therapy. In most cases, serum PSA levels are in the normal range. The 5-year survival rate is less than 40%.
The gross presentation of sarcomatoid carcinoma often resembles that of a sarcoma. Microscopically, sarcomatoid carcinoma contains a glandular component with varying Gleason scores. Its sarcomatoid component tends to consist of nonspecific malignant proliferating spindle cells. Specific mesenchymal components include: osteosarcoma, chondrosarcoma, rhabdomyosarcoma, smooth muscle sarcoma, liposarcoma, angiosarcoma, and many types of heterogenous differentiated components. Sarcomatoid carcinomas should be differentiated from rare types of carcinomas with benign mesenchymal metaplasia of bone or cartilage. Immunohistochemical staining is positive for PSA and/or broad-spectrum keratin in the epithelial component, whereas the spindle cell component is positive for tissue tumor markers and sometimes expresses cytokeratin.
Basal cell carcinoma
Basal cell carcinomas are rare. Basal cell carcinomas of the prostate include malignant basal-like cell hyperplasia (basal-like cell carcinoma) and tumors that somewhat resemble adenoid cystic carcinoma of the parotid gland. It is difficult to classify these proliferative lesions because they are very rare, there are no uniform histologic criteria, and follow-up information is available for only a few cases. In general, basal cell carcinomas are not histologically graded. The limited prognostic data available indicate that a small number of patients die from basal cell carcinoma. This suggests that basal cell carcinoma of the prostate is a potentially aggressive tumor.
Evaluation of prostate cancer after radiation therapy
After radiation therapy, prostate biopsy results should be classified as: no significant cancer, cancer and showing no or only a slight radiotherapy effect, cancer and showing a significant radiotherapy effect, or a combination of all three. Although there are various grading systems for pathology after radiation therapy for prostate cancer, they have not been routinely recommended for clinical use.
Evaluation of prostate cancer after endocrine therapy
In radical prostatectomy specimens, endocrine therapy can result in a significant reduction in prostate cancer volume compared to untreated individuals. In general, tissue response appears to correlate with tumor growth pattern and Gleason score prior to anti-androgen therapy. In addition, morphologic changes were more pronounced after complete anti-androgen therapy than after hormone therapy alone (i.e., luteinizing hormone-releasing hormone analog or anti-androgen therapy). Residual prostate cancer infiltrating the prostatic peritoneum, periprostatic soft tissues and seminal vesicle glands, or metastasizing to pelvic lymph nodes showed a similar response to treatment as prostate cancer confined to the prostate.
After treatment, the tumor may appear as tumor follicles that are wrinkled. Individual infiltrating tumor cells separated by abundant connective tissue may be seen in some areas, and crystals within the glandular lumen are much less common. The cytoplasm of the tumor epithelium is clear due to cell enlargement caused by vacuolar fusion and permeability changes due to cell membrane breakage. The nuclear chromatin showed variable expression, ranging from a slightly condensed state to a densely condensed state, the former barely distinguishing between coarse chromatin granules (heterochromatin) and slender chromatin (euchromatin), while the latter resembled the chromatin changes observed during apoptosis. As demonstrated in post-treatment PIN, apoptotic vesicles were readily found in all epithelial cell layers. Macrophages and detached epithelial cells were seen in the glandular lumen. Untreated adenocarcinoma is characterized by tumor cells with often multinucleated nuclei and distinct nuclei (mean diameter 1.47 μm), nucleolar border clusters, and the presence of a perinuclear halo. In endocrine-treated tumors, the nucleoli are indistinct and small, with an average diameter of 1.09 μm, and in 20% of tumors, the nucleoli are less than 1.0 μm. Tumors with pre-treatment sieve-like, solid/trabecular structures (Gleason score 4 and 5) show less pronounced nuclear and cytoplasmic changes after endocrine therapy than in low-grade glandular vesicles. After treatment, the interstitium shows reduced capillarity, varying degrees of fibrosis, and varying degrees of lymphocytic infiltration, often interspersed with mast cells, plasma cells, and eosinophilic infiltration. Sometimes a foamy histiocytic infiltrate is present, which is difficult to distinguish from the clear cells of prostate cancer.
Periprostatic fibrosis with poorly defined layers of normal structures has been reported after hormone therapy, making surgical treatment more difficult. The longer a patient receives hormone therapy before surgery, the more severe the periprostatic fibrosis becomes. Currently, there are no clear qualitative and quantitative histological studies on the extent of fibrosis and its specific sites after hormone therapy. Based on preliminary morphologic evaluation, periprostatic fibrosis manifests as widened intervals of fibrous connective tissue interspersed in the fatty tissue surrounding the prostate peritoneum. Foci of fibrous connective tissue sometimes appear to completely replace adipose tissue on both sides of the prostate, posteriorly, and around the seminal vesicle gland. This feature cannot exclude the possibility that it represents tumor-induced mesenchymal hyperplasia in which the tumor cells have degenerated after hormone therapy.
Because of the morphologic changes caused by treatment, reliance on the standard Gleason grading criteria for grading residual prostate cancer is inaccurate and therefore not advocated for application.
To summarize
Pathological findings are extremely important for our physicians, especially surgeons, and it is important to obtain the patient’s pathological findings prior to treatment whenever possible. We all know that prostate cancer develops slowly in general, so it is advisable to wait for a certain amount of time to have a prostate puncture.